Guidance for
行业指南
Non-Penicillin Beta-Lactam Risk Assessment:
A CGMP Framework
非青霉素类β-内酰胺类抗生素风险评价：
CGMP框架
DRAFT GUIDANCE
指南草案
This guidance document is being distributed for comment purposes only.
本指南文件仅用于征求社会意见用
TABLE OF CONTENTS
目录
I. INTRODUCTION
I 简介degrade
II. BACKGROUND
II 背景
III. RECOMMENDATIONS
III 建议
I． INTRODUCTION
This guidance describes the importance of implementing appropriate steps during the manufacturing process to prevent cross-contamination of finished pharmaceuticals and active pharmaceutical ingredients(APIs) with non-penicillin beta-lactam antibiotics. This guidance also provides information regarding the relative health risk of, and the potential for, cross-reactivity in the classes of sensitizing
beta-lactam(penicillins and non-penicillin beta-lactams). This guidance is intended to assist manufacturers in assessing whether separate facilities should be used based on the relative health risk of cross-reactivity.
本指南描述了在非青霉素类β-内酰胺类抗生素制剂与原料药生产过程中采取有效措施避免交叉污染的重要性。该指南还提供了不同类别的敏感β-内酰胺（青霉素类和非青霉素类）发生交叉污染的可能性以及健康风险信息。指南的目的在于指导制造商根据交叉污染风险评估来确定药物生产是否需要单独的设备。
Drug cross-contamination is the contamination of one drug with one or more different drugs. Penicillin can be a sensitizing agent that triggers a hypersensitive exaggerated allergic immune response in some people. Accordingly, developing strategies to prevent cross-contamination of other drugs with penicillin is a key element of manufacturing penicillin. Non-penicillin beta-lactam drugs can initiate drug-induced hypersensitivity reactions, including anaphylaxis, an allergic reaction that may be a life-threatening event. As with penicillin, a critical aspect of manufacturing non-penicillin beta-lactam drugs is preventing cross-contamination to reduce the potential for drug-induced, life-threatening allergic reactions.
药物交叉污染是指一种药物污染了一种或者多种的其他药物。青霉素类是能引起很多人产生过激的过敏反应的致敏物质。因此，青霉素类药物的生产关键问题就是要防止青霉素污染其他的药物。非青霉素类β-内酰胺类抗生素也是一种致敏药物，如果污染了其他的药物也可能导致超敏反应，例如过敏反应，而有些过敏反应是能危及到人的生命的。因此，和青霉素一样，非青霉素类β-内酰胺类药物也要防止交叉污染，以减少因交叉污染产生的过敏性反应。
The information in this guidance is intended for manufacturers of finished pharmaceuticals and APIs, including repackagers. Other establishments that handle drugs, such as pharmacy compounders, may find this information useful.
该指南指引的对象包括原料药和制剂的生产制造商，以及药品在包装商。对其他能接触到药物的机构如药品配制机构等也有指导作用。
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA guidance means that something is suggested or recommended, but no required.
FDA的指南文件，包括这份指南，并不具备法律约束力。除非是引用特殊的规定或者是法律条款，指南文件仅仅是FDA现阶段对某一问题的看法，应当仅仅看做是一份建议性文件。FDA
指南文件中的“应该”一词指建议或者推荐，而不是强制要求。
II．BACKGROUND
Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act(21 U.S.C.351(a)(2)(B)) requires that, with few exceptions, all drugs be manufactured in compliance with current good manufacturing practices(CGMPs). Drugs that are not in compliance with CGMPs are considered to be adulterated. Furthermore, finished pharmaceuticals are required to comply with the CGMP regulations at 21 CFR parts 210 and 211.
联邦食品、药品和化妆品管理法501(a)(2)(B)和21 U.S.C.351(a)(2)(B)要求：除极少数情况例外，所有的药品生产都应当符合现行的药品生产质量管理规范（CGMPs）。没有按照CGMPs生产的药品将被视为假药。另外，制剂的生产还要遵循CGMP法规的21章得210和211部分。
Several CGMP regulations directly address facility and equipment controls and cleaning. For example,$211.42(c) requires building and facility controls in general to prevent cross-contamination o
f drug products. Specifically, the regulation states, “there shall be separate or defined areas or such other control systems for firm’s operations as are necessary to prevent contamination or mix-ups” during manufacturing, processing, packaging, storage, and holding processes.
一些CGMP法规明确规定了对设备和仪器的控制与清洗。例如，法规$211.42(c)要求要有对设备和仪器的总体控制以防止药品的交叉污染。应该特别指出的是，法规表明：在药品的生产、加工、包装、储存以及运输的过程中“需要有单独的或规定的区域，或者是其他控制程序以防止交叉污染和混杂”。
With respect to penicillin, $211.42(d) requires that “operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.” However, FDA has clarified that separate buildings may not be necessary, provided that the section of the manufacturing facility dedicated to manufacturing penicillin is structurally , completely and comprehensively separated) from the areas of the facility in which non-penicillin products are manufactured. Under $211.46(d), manufacturers must completely separate air handling systems for
penicillin from those used for other drugs for human use. Similarly,$211.176 requires manufacturers to
test non-penicillin drug products for penicillin where the possibility of exposure to cross-contamination exists, and prohibits manufacturers from marketing such products if detectable levels of penicillin are found.
对于青霉素，$211.42(d)要求“青霉素的生产、加工、包装设施需要和其他的人用药品生产设
施隔离开”。但是，FDA也声明：青霉素生产并不是必须要单独的建筑设施，只要能保证青霉素
的生产设施和其他药品的生产设施在建筑结构上是相互独立的（如，完全和全面地隔开），也是
可行的。$211.46(d)要求：生产商必须对青霉素的生产采用单独的空气处理系统，而不能与其他药
品生产的空气系统混用。同样的，$211.176要求：在有可能存在交叉污染的情况下，生产商必须
检测其他非青霉素类药品中的青霉素含量，如果能在其他药品中检测到青霉素的存在，则禁止出
售该药品。
Although FDA has not issued CGMP regulations specific to APIs, the Agency has provided guidance to API manufacturers in the guidance for industry, ICH Q7, Good Manufacturing Practice Guidance fo
r Active Pharmaceutical Ingredients(ICH Q7 guidance). Because some APIs are sensitizing compounds
that may cause anaphylactic shock, preventing cross-contamination in APIs is as important as preventing cross-contamination in finished products. The ICH Q7 guidance recommends using dedicated production areas, which can include facilities, air handling equipment, and/or processing equipment, in the productin
of highly sensitizing materials, such as penicillins and cephalosporins.
尽管FDA没有发布针对原料药的CGMP指南，但是提供了原料药生产指南：ICH Q7。由于一些
原料药能引起过敏性休克，原料药生产中防止交叉污染和制剂生产一样重要。ICH Q7指南建议生
产高致敏性的原料药，例如青霉素类和头孢菌素类，采用单独的生产区域，包括单独的生产设施、单独的空气处理系统，单独的加工设备等等。
Beta-lactam antibiotics share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond. The side chain variability co
ntributes to antibacterial activity.
β-内酰胺类抗生素具有共同的基础化学结构，包括一个含3个C和1个N的环状氨基的β-
内酰胺环。与β-内酰胺环相关的侧链通过肽链和主结构相连，为可变基团。侧链的变化能影响抗
生素的抗菌活性。
As of the date of this publication, FDA has approved over 34 beta-lactam compounds as active ingredients in drugs for human use. Beta-lactam antibiotics include the following five classes: ·, ampicillin, oxacillin)
·, cephalexin, cefaclor)
·, meropenem)
·, loracarbef)
·, aztreonam)
截止到本指南发布的日期止，FDA已经批准了超过34个β-内酰胺类化合物作为人用药的活性成分。β-
内酰胺类抗生素包括下面的五类：
·青霉素类（如，青霉素，苯唑西林）
·头孢菌素类（如，头孢氨苄，头孢克洛）
·青霉烯类（如，美罗培南）
·碳头孢烯类（如，氯碳头孢）
·单环菌素类（如，氨曲南）
The penicillins ,cephalosporins, penems, and carbacephems share a characteristic bicyclic core structure, which is believed to initiate allergic reactions. The monobactam aztreonam has a unique monocyclic beta-lactam nucleus and rarely cross-reacts with penicillins and cephalosporins. Aztreonam and ceftazidime have a common side chain, and cross-reactivity between aztreonam and ceftazidime has been reported.
青霉素类、头孢菌素类、青霉烯类、碳头孢烯类都有共同的二环结构，该结构被认为与致敏反应有主要关系。单环菌素类的氨曲南是唯一单环β-内酰胺类抗生素，极少与青霉素类和头孢菌素类发生交叉反应。氨曲南和头孢他啶具有相同的侧链结构，有报道称氨曲南和头孢他啶能发生相互作用。
Beta-lactam antibiotics inhibit bacterial cell wall synthesis. Many bacteria produce beta-lactamases, which are enzymes that degrade and inactivate beta-lactam antibiotics. Beta-lactam compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity but are irreversible inhibitors of many beta-lactamases; they are used in combination with specific beta-lactam agents to preserve antibacterial activity.
β-内酰胺类抗生素能够抑制细菌细胞壁的生长。许多细菌能产生β-内酰胺酶，这种酶能够降低β-内酰胺类抗生素的活性。β-内酰胺类得活性物质如克拉维酸、三唑巴坦和舒巴坦等抗菌活性较弱，但是这些物质能够不可逆地许多β-内酰胺酶，因此他们经常混合其他β-内酰胺类药物一起使用以确保抗菌活性。
Allergic reactions associated with penicillins and non-penicillin beta-lactam antibiotics range from rashes to life-threatening anaphylaxis. Immunoglobulin E(IgE) antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives, and anaphylactic shock. IgE-mediated hypersensitivity reactions are of primary concern because they may be associated with significant morbidity and mortality. There is evidence that patients with a history of hypersensitivity to penicillin may also experience IgE-mediated reactions to cephalosporins and penems. Cross-reactivity(cross-sensitivity) between beta-lactam products has been and continu
es to be a major concern in the manufacture of drugs.
青霉素类和非青霉素类抗生素可能引发包括从皮疹到危及生命的过敏症等不同程度的过敏反应。其中由免疫球蛋白（IgE）导致的超敏反应相关症状主要包括枯草热、哮喘、荨麻疹以及过敏性休克，这类过敏反应由于发病率和死亡率高，是使用β-内酰胺类抗生素最应关注的问题。有证据证明有青霉素过敏史的患者在使用头孢菌素类和青霉烯类抗生素时也可能发证这类IgE介导的

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